Microbial ureases are important enzymes in certain human and animal pathogenic states, in ruminant metabolism and in environmental transformation of certain nitrogenous compounds.
Bacterial urease is implicated in the pathogenesis of many clinical conditions. It is directly associated with the formation of infection stones and contributes to the pathogenesis of pyelonephritis, ammonia encephalopathy, hepatic coma, urinary catheter encrustation and peptic ulceration. Bacterial urease in feces also plays a prominent role in diaper dermatitis (also known as diaper rash). This invention attempts to ameliorate two of these conditions, namely; gastrointestinal diseases associated with H. pylori and diaper dermatitis.
H. pylori is presently being studied and has been implicated in several gastrointestinal diseases. Formerly known as Campylobacter pylori or Pylordis, this organism was first isolated from humans in 1982. The Principals and Practice of Infectious Diseases, Update No. 9 (1991) pages 1-10 contains a cumulative description of the characteristics H. pylori and its association with gastrointestinal disease. In particular, these organisms have been implicated in chronic diffuse and Type A gastritis as well as gastric and duodenal ulcers.
Since H. pylori is closely associated with chronic gastritis, which in turn is a well-known risk factor for the development of gastric carcinoma, it has been postulated that there is a role for this organism in the development of such carcinomas. A number of recently published studies appears to further confirm that H. pylori is a risk factor in the development of gastric cancer. (Parsonnet, et al. New Eng. J. Med., Oct. 1991: 1127-1131; Nomura, et al., New Eng. J. Med., Oct. 1991: 1132-1136).
The organism has been isolated from the gastric environment, which is generally hostile to bacterial growth, and it has further been postulated that the organism colonizes the gastric mucosa and generates a protective layer or sheath which contains ammonia, which shields the microorganism from acid inactivation. While it has not been mentioned in the literature, we believe that bicarbonate ions also offer a measure of protection to the organism in this environment.
At present there is no fully accepted therapy for the eradication of H. pylori. The most widely used approach in research studies is a combination therapy employing a bismuth salt and one or two antibiotics such as metronidazole, amoxicillin or tetracycline. These therapies are not fully successful, and run the risk of adverse effects such as medication-induced upper GI symptoms, antibiotic-associated colitis and candidiasis. Therefore, one objective of the present invention is to provide a new and superior method to minimize or eradicate the presence or activity of H. pylori in the gastrointestinal tract. As such, it is believed that treatment and eradication of H. pylori reduces the incidence or severity of gastritis and ulcer disease and as a result may also remove a causative factor for the development of gastric carcinoma.
The present invention also relates to the treatment of skin rash or dermatitis caused or aggravated by urease containing bacterial organisms, components of such organisms and compounds produced by such organisms.
Few infants or incontinent adults escape several episodes of such irritant induced contact dermatitis, which is generally known as diaper rash or diaper dermatitis. This is a common occurrence since the diapered skin is frequently exposed to a warm, moist environment and increases in the hydration of the skin, which cause increased friction, abrasion and permeability. In addition, under these circumstances the microbial count also rises.
For many years the prevailing explanation for the development of diaper rash involved the bacterial decomposition of urine with the formation of ammonia, which was considered to be the primary irritant. The work of Layden et al. Arch Dermatol. 113:1678-1680 (1977), however, suggested that ammonia per se was not a primary factor in the induction of this condition.
As a result of recent experimental work, an indirect role has been assigned for the ammonia resulting from the interaction of the fecal urease containing bacteria and urine. In this model, the direct irritation effect on the skin can be attributed to fecal enzymes, particularly proteases and lipases. These enzymes become more active and thus more damaging as the pH increases. The increase in pH is the result of ammonia production from urinary urea through the action of fecal urease. Also, while not generally acknowledged in the literature, the bicarbonate ions generated as a result of urea hydrolysis, also tend to increase the pH.
Since urine and feces are commonly present in the diaper at the same time, and exposure to the skin for several hours is not uncommon, suitable conditions and ample time are available for this interaction and the resulting skin damage to occur.
This type of dermatitis can range in severity from mild erythema to severely inflamed tissue with secondary bacterial infection.
The most common treatment for diaper rash is directed toward cleaning and drying the involved area. According to this regime, the soiled diaper should be changed as soon as possible and talcum powder, corn starch or another such product is applied to the affected area.
Since the enzymes which actually cause skin irritation are believed to be potentiated by ammonia and bicarbonate, reducing the presence or activity of these compounds and/or the urea substrate should reduce the incidence of diaper dermatitis. Further, keeping the enzymes away from the skin should also lead to a positive outcome. Consequently, another object of the present invention is to provide a composition which reduces the incidence or severity of such dermatitis.